Project Summary The rising prevalence of obesity in developed countries has shown no signs of abating, putting society under monumental strain. The burden is both monetary and health-related, as obesity is a strong risk factor for the development of type II diabetes and its associated complications: coronary heart disease and stroke. Great progress has been made in our understanding of the pathology of obesity-related diseases, yet it is becoming clear that new approaches are needed to find pharmacological targets to treat metabolic dysfunction in a more effective way and with less side effects. One such approach is to target the function of adipose tissue, the organ at the forefront of metabolic disturbances in obesity. Adipose tissue produces a number of secreted factors that have profound effects on systemic metabolism. Most notably, adiponectin (Apn), which has been shown to have positive effects on insulin sensitivity and inflammation in obese mice. In fact, serum adiponectin is reduced in the obese state, an effect that has been shown to contribute to obesity-associated disease. To date, it has been challenging to find a practical way to harness the benefits of adiponectin. We have recently uncovered a regulatory mechanism that functions to limit adiponectin expression in adipocytes. In this project, I propose that if we can further understand this mechanism, we can find new therapeutic avenues to restore diminished adiponectin levels in obesity and, along with that, enhance systemic insulin sensitivity and reduce inflammation. We have generated the first transgenic mouse model that allows us to inducibly overexpress adiponectin in any tissue. Induction of Apn mRNA in liver or kidney resulted in the expected increase in serum Apn. Interestingly, induction of Apn in adipose tissue resulted in a decrease in serum Apn. Herein, I will detail this preliminary data and the experimental design to characterize this mechanism that restrains Apn expression specifically in the adipocyte and determine the efficacy of restoring Apn after the onset of obesity for enhancing insulin sensitivity.